Method of treatment of artherosclerosis and balloon catheter the same

ABSTRACT

A method for the treatment of atherosclerosis in a mammal by destruction of atheromatous plaque is disclosed. The disclosed method includes injecting a hematoporphyrin into the mammal for selective uptake into the atheromatous plaque, and delivering light to the diseased vessel so that the light activates the hematoporphin for lysis of the plaque. The preferred method utilizes a balloon catheter equipped with flexible optical fibers for transmission of light from an external source for illumination of the interior of the inflated balloon. By inflation of the balloon, the opaque blood between the balloon and the atheromatous plaque is displaced to facilitate activation of the hematoporphyrin. The balloon may be illuminated and inflated and deflated in a cycle responsive to the patient&#39;s pulse so as to minimize interference with blood flow.

This is a continuation of copending application Ser. No. 881,588 filedon 7/2/86 now abandoned which is a continuation of copending applicationSer. No. 838,393 filed on 3/5/86 now abandoned which is a continuationof copending application Ser. No. 721,995 filed on 4/11/85 now abandonedwhich is a divisional of Ser. No. 443,958 filed on 11/23/82 now U.S.Pat. No. 4,512,762.

BACKGROUND OF THE INVENTION

Atherosclerosis is a coronary disease wherein fatty substances (lipids),hereinafter referred to as atheromatous plaques, form deposits in andbeneath the intima which is the innermost membrane lining arteries andveins. Atherosclerosis tends to involve large and medium-sized arteries.Most commonly affected are the aorta and the iliac, femoral, coronary,and cerebral arteries. Clinical symptoms occur because the mass of theatherosclerotic plaque reduces blood flow through the involved arteryand thereby compromises tissue or organ function distal to it.

Modern treatment of atherosclerosis revolves around highly sophisticatedcoronary care units. In general, modern medicine follows one of twoapproaches to the care of patients suffering from atheroscleroticcomplications: either (1) the diseased vascular segments are replacedwith prosthetic or natural grafts, even going as far as hearttransplantation or (2) drugs such as antiarrhythmic agents,anticoagulants and plasma lipid lowering agents are administered toenable the patient to live with the condition. Neither approachcontemplates a cure of the diseased members.

SUMMARY OF THE INVENTION

The present invention provides for treatment of a main artery or otherblood vessel afflicted with atherosclerosis. The method involvesadministration of a hematoporphyrin, preferably by intravenousinjection, to the mammal to be treated. The invention resides, in part,in the discovery that the hematoporphyrin so administered is selectivelyabsorbed into the atheromatous plaque, with little or no absorption intohealthy areas of the arterial wall. Upon illumination of theatheromatous plaque, containing absorbed hematoporphyrin, thehematoporphyrin is activated and destroys the host atheromatous plaquetissue. Illumination of the plaque may be achieved with either one oftwo different techniques. With one technique, the patient iscatheterized with a light-emitting catheter inserted into the diseasedartery or other vessel so that the light-emitting portion of thecatheter is adjacent the atheromatous plaque. Alternatively, a form ofliquid light is injected into the vascular tree such that the liquidlight, which mixes freely with blood or a blood replacement, perfusesthe diseased artery.

In the preferred embodiment a special light-emitting balloon catheter isemployed. The balloon catheter includes an inflatable balloon secured toone end of the catheter tube, for inflation of a gas from a remotesource, and optical fibers which extend through the tube lumen fortransmission of light from an external light source to the interior ofthe balloon. Preferably, the light-transmitting optical fibers areoptically joined to a light scattering device within the balloon in theform of a hollow, liquid-filled fiber or tube. The liquid filling isselected for optimum transmission of light and maximum light scattering.

Use of the preferred balloon catheter provides for displacement of thelight-opaque blood between the external balloon surface and theatherosclerosis plaque by inflation of the balloon. Use of the preferredcatheter also allows for intermittent and cyclical illumination andinflation/deflation of the balloon so as to minimize interruption ofblood flow to the vital organs and to avoid potential problems attendentto heating of the balloon material and the blood of the mammalundergoing treatment.

Activation of hematoporphyrin within atheromatous plaques may also beachieved by injecting a form of liquid light into the vascular tree.Examples of light-emitting liquids are the bioluminescent system offirefly lucerin/lucerase and the chemiluminescent system of the CyalumeLightstick manufactured by the American Cyanamid Company. Although theorganic liquid-based Cyalume Lightstick is incompatible with blood, anaqueous liquid-based chemiluminescent system has recently beendeveloped. See "Aqueous Peroxyoxalate Chemiluminescence, Final Report tothe Office of Naval Research, Contact N00014-77-C-0634" by A. G. Mohanet al. at the American Cyanamid Company, Bound Brook, N.J., January,1982. Although the light intensity of any liquid light is less than thatwhich is achievable with the fiberoptic delivery of a laser, activationof hematoporphyrin is a function of the product of light intensity timesthe duration of illumination, so that a relatively low level of lightintensity for a long duration is sufficient to activate hematoporphyrin.A potential advantage of the use of liquid light is that all diseasedvessels can be perfused with the liquid light, once intravascularinjection of the liquid light and mixing with blood have been completed.Knowledge of the exact location of atheromatous plaques would beunnecessary, since all plaques would be exposed to the light. Shouldblood prove to be too light-opaque to allow a sufficient quantity oflight to reach a plaque, blood replacement with more translucentliquids, such as perfluorocarbon emulsion-containing blood substitutes,may be performed prior to injecting the liquid light. For an example, inanimals, of total blood exchange with perfluorocarbon chemicals, seeGollan et al, Am J. Physiol 229:1045 (1975). Fluosol-DA, a commerciallyavailable perfluorocarbon-containing blood substitute from AlphaTherapeutics, a subsidiary of the Green Cross Corporation, is currentlyundergoing clinical trials and has been used for massive transfusions inpatients with a remarkable lack of side effects.

Since both the firefly luciferin/lucerifase system and the aqueousperoxyoxylate system can be too toxic in the doses that are required toactivate hematoporphyrin within atheromatous plaques, the toxicity ofthese systems can be reduced markedly by modifications such asmicroencapsulation of some or all of the reactants in these liquids.

Accordingly, it is an object of the present invention to provide amethod for treatment of atherosclerosis by destruction of theatheromatous plaque.

It is a further object of the present invention to provide a catheterfor transmission of activating light directly into atheromatous plaqueby displacement of light-opaque blood between the light-emitting portionof the catheter and the atheromatous plaque.

It is yet a further object of the present invention to illuminateartheromatous plaques, containing absorbed hematoporphyrin, with minimalinterruption of the flow of blood to the vital organs.

Yet another objective is to illuminate atheromatous plaques with minimalelevation of the temperature of the mammal's blood.

Yet another objective is to illuminate atheromatous plaque by perfusingthe diseased vessel with liquid light.

Other objects and further scope of applicability of the presentinvention will become apparent from the detailed description to follow,taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of use of the preferred catheter,inserted into a main artery of a patient, for treatment ofatherosclerosis in accordance with the present invention; and

FIG. 2 is a schematic representation of the use of a second type ofilluminating catheter in the treatment of atherosclerosis in accordancewith the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term "hematoporphyrin", as used herein, is intended to encompasshematoporphyrin and its derivatives which are preferentially taken upinto atheromatous plaque and which respond to a source of light todestroy the host cell tissue.

The preferred hematoporphyrin is the acetic acid-sulfuric acidderivative of hematoporphyrin prepared, for example, as described byRichard L. Lipson and Edward J. Baldes in "The Photodynamic Propertiesof a Particular Hematoporphyrin Derivative", Arch. Derm. 82(4) 508-516,1960 and by Richard L. Lipson et al in "The Use of a Derivative ofHematoporphyrin in Tumor Detection", J. Natl. Cancer Inst. 26(1):1-8,1961. In general the method of Lipson et al involves admixing a "crude"recrystallized hematoporphyrin with a mixture of 19 parts glacial aceticacid and one part concentrated sulfuric acid, followed by filtration toseparate and remove the undissolved residue. The solution is thenneutralized, e.g. with of 3% sodium acetate solution, to precipitate outthe hematoporphyrin derivative (HPD). This hematoporphyrin derivative isrecognized by the trade designation HPD and is commercially availablefrom Oncology Research and Development, Inc. In practicing the presentinvention, the HPD is used in the commercial form and is not diluted inany way.

Sanderson et al, in "Hematoporphyrin as a Diagnostic Tool" Cancer 30(5)1368-72 (1972) report that this hematoporphyrin derivative (HPD) showsmaximum fluorescence upon illumination with violet light within a wavelength range of about 400 to 410 nm. HPD exhibits wide band absorbtionat about 500 nm with small peaks at about 635 nm. For the purposes ofthe present invention, the preferred activating illumination for thehematoporphyrin derivative (HPD) is a monochromic red light at about 635nanometers because light at this wavelength penetrates tissue; and, thepreferred source for such illumination is a dye laser.

It has been well known for many years that HPD accumulates in malignanttumors after intravenous injection and that HPD fluorescence, uponexposure to ultraviolet light, facilitating tumor localization. Theaforementioned articles by Lipson et al report on such findings. Morerecently, the cytotoxic effect of HPD activated by light has been usedto destroy malignant tumors in man as well as in animals. Since normaltissues surrounding malignant tumors absorb relatively small amounts ofHPD, little or no damage to these tissues occurs upon exposure to light.See, e.g. "Photoradiation in the Treatment of Recurrent BreastCarcinoma", T. J. Dougherty et al, J. Natl, Cancer Inst. 62(2):231-237(1979).

In accordance with the present invention, it recently has beendiscovered that HPD is selectively concentrated in atheromatous plaquesin the aorta of rabbits following intravenous injection. Atheromatousplaques were found to fluoresce strongly when exposed to ultravioletlight, while the normal plaque-free aortic wall demonstrated nofluorescence. Since atheromatous plaques consist primarily of cellswhich are engorged with lipids and other materials, destruction of thesecells by photoactivation of HPD results in lysis of such plaques. It isbelieved that, upon exposure to activating illumination, thehematoporphyrin produces singlet oxygen which causes cell destruction.Thus, the present invention involves photodynamic destruction of theatheromatous plaques by activation of plaque-absorbed hematoporphyrin bya process which may be characterized as photoatherolysis.

The preferred catheter of the invention is illustrated in FIG. 1. In therepresentation of FIG. 1 the wall of the main artery undergoingtreatment is represented by the numeral 10. For treatment, the mammal iscatheterized with insertion of the light-emitting portion of thecatheter into the diseased blood vessel to a position adjacent thedeposit of atheromatous plaque to be lysed. FIG. 1 depicts the preferredcatheter positioned in this manner. The preferred catheter includes alumen tube 12 and a balloon member 14 affixed to its distal end with theinterior of the balloon opening into the lumen of the catheter tube.FIG. 1 depicts the balloon 14 in its inflated state with its exteriorsurface in direct contact with the atheromatous plaque 16 to be lysed.The deflated state of the balloon is indicated by the dotted line 18.Inflation of the balloon is provided for by the lumen of the catheterwhich is in fluid communication with the interior of the balloon andwhich may be connected, at its opposite end, to a source of pressurizedgas. At least one optical fiber 20 is provided for transmitting lightfrom an external source to liquid 22 contained in a hollow glass fiber24. The liquid 22, for example one of many refractive index liquidscommercially available from Cargille Laboratories, functions to transmitthe scatter light throughout the interior of balloon 14. A movableguidewire 28 extends through the center of the lumen of the cathetertube and through the center of the hollow glass fiber. The distal end ofthe guidewire 28 extends a variable distance beyond the distal end ofthe balloon 14.

FIG. 2 depicts the use of a catheter which is not provided with aballoon but which is otherwise similar. In FIG. 2, correspondingcomponents of the catheter are represented by like numerals. A catheterof this design may be particularly advantageous for use in smallvessels, such as coronary arteries, wherein displacement of therelatively small volume of blood with a balloon may be unnecessary forlight to be transmitted to a plaque.

A particularly advantageous feature of the preferred catheterillustrated in FIG. 1 is the capability for delivering light to theplaque in an intermittent fashion. Intermittent light transmission,synchronized with intermittent balloon inflation, is advantageous when aprolonged exposure of a plaque to light within and to a vital organ isrequired. For example, inflation of the balloon with a low viscosity gasduring the only one part of each cardiac cycle, may be performedutilizing counterpulsation circulatory assist devices, and can besynchronized with light transmission, so that a long total, additiveexposure of a plaque to light may be achieved without significantcompromise of blood flow. Although light may be transmitted continuouslyalong the optical fiber and exposure of the plaque to light would thenoccur only when inflation of the balloon is sufficiently great todisplace intervening blood, intermittent transmission of the light alongthe fiber would be advantageous when the light intensity required wouldresult in heating the balloon material and/or blood. For example, athick plaque may require an intense light in order to activate HPD deepwithin the plaque. The heat produced by the light could adversely affectthe balloon material and/or blood within the artery. Intermittenttransmission of light would allow both the balloon material and the gaswithin the balloon to be cooled intermittently by the flow of blood pastthe balloon during balloon deflation. A period of 30 minutes or more maybe required to photoactivate HPD deep within a plaque. However,obstruction of blood flow with the balloon inflated continuously forsuch a length of time cannot be performed within arteries to vitalorgans without deliterious effects. In such a case ECG-gated,intermittent balloon inflation, as is commonly performed with anintra-aortic balloon used in a counterpulsation circulatory assistdevice, may be employed so as not to interfere with blood flow to vitalorgans, while at the same time permitting a prolonged exposure of aplaque to light.

Others skilled in the art of fabrication of optical fibers and cathetersmay proffer many modifications of the basic design of the preferredcatheter. For example, the optical fiber 20 may terminate withoutcoupling to any other fiber; a properly designed lens at the terminalend of the optical fiber 20 might be used to disperse light over theinternal surface of the artery. Alternatively, the optical fiber 20 maybe coupled, at its distal end, to a specially designed solid fiber whichwould be used to disperse light along all or a portion of its length.

In accordance with the present invention, it has been discovered thataqueous peroxyoxylate chemiluminescent liquids manufactured by theAmerican Cyanamid Company may be injected into the bloodstream of ratsand rabbits without producing any side effects. The liquid reactantstypically include a triflyl oxamide and hydrogen peroxide along withsulfonated rubrene as a fluorescer and Deceresol NI as a surfactant. Aquantum yield of the reaction of 7% with a light capacity of 62 lumenhours per liter of solution was reported recently by A. G. Mohan et alin "Aqueous Peroxyoxalate Chemiluminescence: Final Report to the Officeof Naval Research, Contract N0014-77-C-0634." This quantity of light isconsiderably more than that needed to activate hematoporphyrin. Thus,the injection of the chemiluminescent liquid light into the vasculartree of mammals can be performed for activation of hematoporphyrinwithin atheromatous plaques for lysis all of plaques throughout thevascular tree.

Another form of liquid light which can be injected into the bloodstreamof mammals is the well-known firefly lucerin/lucerifase bioluminescentsystem. Luciferin and luciferase are water soluble, and light is emittedwhen adenosine triphosphate, which is also water soluble, is added tothese substances. A buffer such as glycine and the metal ion, magnesium,are usually present in the solution to facilitate the reaction.Intravenous injection of these materials, obtained commercially fromSigma Chemical Company, into dogs has produced no deliterious sideeffects.

If the light-opacity of blood prevents a sufficient quantity of light,in the form of liquid light, to activate hematoporphyrin within anathermatous plaque, replacement of blood with a more translucent bloodsubstitute may be performed. Examples would include normal saline,dextrose in water, and Frales-Linger solution. For replacement of bloodwithin the entire vascular tree or within blood vessels to vital organs,perfluorocarbon emulsion-containing blood substitutes, such asFluosol-DA, may be used. Fluosol-DA carries oxygen in a manner similarto hemoglobin and has been approved by the FDA for use in clinicaltrials. For examples of the use of Fluosol-DA as a blood substitutes,see Engelman et al, Ann Thorac Surg 32: 528-535 (1981), Kanter et al,Circulation 64:75-83 (1981).

An advantage in the use of liquid light of activate hematophorphyrinwithin atheromatous plaques is that, once the liquid light has mixed insufficient quantity with blood or a blood substitute throughout thevascular tree, it would be unnecessary to know the location of theplaques in order to lyse all plaques within the entire vascular tree. Another advantage is that a catheterization procedure would be unnecessaryto deliver the light to a plaque in a vessel segment of interest.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrated and not restricted, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

I claim:
 1. A balloon catheter for use in applying energy to a wall ofan artery for medical treatment, said catheter comprising:a tubedefining a lumen; an inflatable balloon secured to the distal end ofsaid tube for inflation from a remote source of fluid, said balloonbeing configured so that said tube may be navigated through the arterywhen deflated and allow blood flow while said tube is being navigatedwith the balloon in a deflated state and also configured to displaceblood within the artery when inflated; fiber optic means connectable toan energy source at the proximal end and extending through said lumen toemit energy into the balloon for transmission of energy from an externalenergy source to the interior of said balloon; and means for diffusingenergy that is transmitted by said fiber optic means, said means fordiffusing energy being in optical communication with said fiber opticmeans and being within said balloon so that the energy transmitted intosaid balloon via the fiber optic means may be applied through saidballoon to all part of the walls of the artery surrounding said balloonsimultaneously.
 2. The balloon catheter of claim 1 wherein the means fordiffusing energy is an elongated hollow member within and coextensivewith the length of said balloon and forming a junction with said fiberoptic means, said elongated hollow member being filled with a fluid forscattering light throughout the interior of said balloon and to thewalls of the artery.
 3. The balloon catheter of claim 2 furthercomprising a guide wire extending through the center of said lumen andthrough the center of said elongated hollow member and extending avariable distance beyond the distal end of said balloon for facilitatinginsertion and positioning of the catheter within an artery.
 4. Theballoon catheter of claim 2 wherein said fluid is a refractive indexliquid.
 5. The balloon catheter of claim 1 wherein said means fordiffusing energy is a lens positioned at the terminal end of said fiberoptic means.
 6. The balloon catheter of claim 1 wherein said means fordiffusing energy is a solid fiber coupled at the terminal end of saidfiber optic means capable of dispersing light along all or a portion ofits length.
 7. A method for applying energy to the walls of an artery tobe treated so that the energy emitting portion of the catheter isadjacent the part of the artery to be treated, the catheter comprising:atube defining a lumen, an inflatable balloon secured to the distal endof the tube for inflation from a remote source of fluid, the balloonbeing configured so that the tube may be navigated through the arterywhen the balloon is deflated and allow blood flow while the tube isbeing navigated with the balloon in a deflated state and also configuredto displace blood within the artery when inflated, fiber optic meansconnectable to an energy source at the proximal end and extendingthrough said lumen to emit energy into the balloon for transmission ofenergy from an external energy source, and means for diffusing energythat is transmitted by said fiber optic means, said means for diffusingenergy being in optical communication with the fiber optic means andbeing within said balloon so that energy transmitted into the balloonvia the fiber optic means may be applied through the balloon to allparts of the walls of the artery surrounding the balloon simultaneously;(B) displacing blood in the artery between the energy emitting catheterand the portion of the artery to be treated by inflating the balloon;(C) energizing the entire balloon surface of the energy emittingcatheter by diffusing energy through the means for diffusing energy toenable the entire balloon surface to transmit energy to all parts of thewalls of the surrounding artery simultaneously; and (D) deflating theballoon of the light emitting catheter and removing the light emittingcatheter after treatment.
 8. The method of claim 4 wherein the step ofdisplacing blood by inflating the balloon of the energy emittingcatheter illuminates the walls of the artery with an intensity greaterthan would be the case when blood is present in the artery.
 9. Themethod of claim 8 wherein the balloon inflation is intermittent.
 10. Themethod of claim 9 wherein the balloon is intermittently inflatedresponsive to ECG-gating so as to allow prolonged exposure of the siteto the transmitted energy and to enable the treatment of the walls ofthe artery without compromising the patient from disruption of bloodflow.
 11. The method of claim 9 wherein the balloon energizing occursonly when the balloon is inflated.
 12. The method of claim 7 whereinenergy is transmitted from an external light source to energize theinterior of the balloon of the energy emitting catheter and all parts ofthe walls of the surrounding artery simultaneously.
 13. The method ofclaim 7 wherein the insertion of the catheter in an artery isfacilitated by a guide wire extending through the center of the lumenand of the elongated hollow member of the energy emitting catheter andextending a variable distance beyond the distal end of the balloon ofthe catheter.
 14. The method of claim 7 wherein the energy is maximizedby transmitting energy through diffusing means comprising an elongatedhollow member within and coextensive with the length of the balloon andforming an optical junction with the fiber optic means with a liquidfilling the elongated hollow member for scattering energy through theinterior of the balloon.
 15. The method of claim 7 wherein the energy ismaximized by transmitting energy through diffusing means comprising alens positioned at the terminal end of the fiber optic means in theenergy emitting catheter.
 16. The method of claim 7 wherein the energyis maximized by transmitting energy through diffusing means comprising asolid fiber coupled at the end of the fiber optic means capable ofdispersing energy along all or a portion of its length.
 17. The methodof claim 7 wherein the external energy source which is connected to thefiber optic means is a source of ultraviolet light.
 18. The ballooncatheter of claim 1 further comprising means to intermittently inflatesaid inflatable balloon responsive to ECG-gating so as to allowprolonged exposure of the site to the transmitted energy and to enabletreatment of the walls of the artery without compromising the patientfrom disruption of blood flow.
 19. A balloon catheter for displacingblood within an artery to enable the wall of the artery to beilluminated for medical treatment while reducing the amount of lightlost through the blood which would otherwise occur comprising:a tubedefining a lumen, said tube being configured to navigate an artery; aninflatable balloon secured to one end of said tube for inflation from aremote source of gas, said balloon being configured so as not tointerfere with the navigation of said tube through the artery whendeflated and allow blood flow while said tube is being navigated withthe balloon in a deflated state and also configured to displace bloodwithin the artery when inflated; fiber optic means connectable to alight source at the proximal end and extending through said lumen andinto the balloon for transmission of light from an external light sourceto the interior of said balloon and to the walls of the artery forilluminating the walls of the artery, when blood is displaced, with anintensity greater than would be the case when blood is present in theartery; an elongated hollow member within and coextensive with thelength of said balloon and forming an optical junction with said fiberoptic means; a liquid filling said elongated hollow member forscattering light throughout the interior of said balloon and to thewalls of the arteries; and a guidewire to which the distal end of saidballoon is affixed; said balloon and fiber optic means enabling thewalls to be illuminated by displacing blood so that the light from thefiber optic means reaches the walls of the artery for treatment ofatheromatous plaque, and said inflatable balloon and said fiber opticmeans enabling the transmission of light to be synchronized forintermittent displacement of blood from a selected sight in the arteryat the same time as light is transmitted so as to allow prolongedexposure of the sight to the transmitted light and to enable thetreatment of the walls of the arteries without compromising the patientfrom disruption of blood flow.